› Dr Daniel Ricklin
E: ricklin@upenn.edu
T: (215)-746-5760
F: (215)-573-8738
W: http://www.med.upenn.edu/apps/faculty/index.php/g275/p8138788

Daniel Ricklin, Ph.D.



Current Position

Research Assistant Professor

Education

Ph.D, University of Basel, Molecular Pharmacy Group (2005)

M.Sc, Swiss Federal Institute of Technology (ETH), Pharmaceutical Sciences (1999)


Research

The primary focus of my research efforts is on the molecular elucidation of the role of the human complement system in health and disease. In recent years, a body of research has impressively demonstrated that the function of the complement system reaches far beyond the detection and elimination of microbial intruders but covers a broad range from immune modulation and metabolism to cell development and homeostasis, which require a highly tailored and context-specific response. Using an integrated approach based on biophysical (e.g., surface plasmon resonance), biochemical, structural, and cell-based techniques, my goal is to shed light into the underlying processes of complement activation and regulation, as well as to describe its molecular connections to associated physiological pathways. At the same time, it has become evident that any disruption of the careful balance between activation and regulation may contribute to pathological processes, and a number of complement-related diseases have been described in recent years and put complement-directed drug discovery into the spotlight. At the same time, complement is also involved in adverse effects observed in connection with the emerging field of biomaterials in modern medicine (e.g., implants, drug delivery devices). One aspect of my research therefore focuses on the discovery and development of potent inhibitors that allow for a therapeutic modulation of the complement cascade at various stages, and on the evaluation of such inhibitors in clinically relevant models. Finally, I am investigating the fascinating immune evasion mechanisms that human pathogens developed through millennia of co-evolution with their host. Focusing on Staphylococcus aureus, I examine various bacterial inhibitors directed against complement and other immune pathways, and explore their implications on immune activity and their potential as templates for therapeutics.



Publications

Wu J, Wu YQ, Ricklin D, Janssen BJ, Gros P, Lambris JD. (2009). Structure of complement fragment C3b-factor H and implications for host protection by complement regulators. Nature Immunology 10: 728-33. Additional Links: Supplementary Information.
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Schuster MC, Ricklin D, Papp K, Molnar KS, Coales SJ, Hamuro Y, Sfyroera G, Chen H, Winters MS, Lambris JD. (2008). Dynamic structural changes during complement C3 activation analyzed by hydrogen/deuterium exchange mass spectrometry. Molecular Immunology 45: 3142-51 .
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Hammel M, Sfyroera G, Ricklin D, Magotti P, Lambris JD, Geisbrecht BV. (2007). A structural basis for complement inhibition by Staphylococcus aureus. Nature Immunology 8: 430-7 . Additional Links: Science Editor's Choice.
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Hammel M, Sfyroera G, Pyrpassopoulos S, Ricklin D, Ramyar KX, Pop M, Jin Z, Lambris JD, Geisbrecht BV. (2007). Characterization of Ehp, a secreted complement inhibitory protein from Staphylococcus aureus. The Journal of Biological Chemistry 282: 30051-61 .
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Garcia BL, Tzekou A, Ramyar KX, McWhorter WJ, Ricklin D, Lambris JD, Geisbrecht BV. (2009). Crystallization of human complement component C3b in the presence of a staphylococcal complement-inhibitor protein (SCIN). Acta crystallographica. Section F, Structural biology and crystallization communications 65: 482-5.
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Ricklin D, Tzekou A, Garcia BL, Hammel M, McWhorter WJ, Sfyroera G, Wu YQ, Holers VM, Herbert AP, Barlow PN, Geisbrecht BV, Lambris JD. (2009). A molecular insight into complement evasion by the staphylococcal complement inhibitor protein family. Journal of Immunology 183: 2565-74 .
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Chen H, Ricklin D, Hammel M, Garcia BL, McWhorter WJ, Sfyroera G, Wu YQ, Tzekou A, Li S, Geisbrecht BV, Woods VL, Lambris JD. (2010). Allosteric inhibition of complement function by a staphylococcal immune evasion protein. Proceedings of the National Academy of Sciences of the United States of America 107: 17621-6:. Additional Links: Supplementary Information.
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Rooijakkers SH, Wu J, Ruyken M, van Domselaar R, Planken KL, Tzekou A, Ricklin D, Lambris JD, Janssen BJ, van Strijp JA, Gros P. (2009). Structural and functional implications of the alternative complement pathway C3 convertase stabilized by a staphylococcal inhibitor. Nature immunology 10: 721-7. Additional Links: Supplementary Information.
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Magotti P, Ricklin D, Qu H, Wu YQ, Kaznessis YN, Lambris JD. (2009). Structure-kinetic relationship analysis of the therapeutic complement inhibitor compstatin. Journal of Molecular Recognition 22: 495-505 .
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Ricklin D, Ricklin-Lichtsteiner SK, Markiewski MM, Geisbrecht BV, Lambris JD. (2008). Cutting edge: members of the Staphylococcus aureus extracellular fibrinogen-binding protein family inhibit the interaction of C3d with complement receptor 2. Journal of Immunology 181: 7463-7 .
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Wu YQ, Qu H, Sfyroera G, Tzekou A, Kay BK, Nilsson B, Nilsson Ekdahl K, Ricklin D*, Lambris JD*. (2011). Protection of nonself surfaces from complement attack by factor h-binding peptides: implications for therapeutic medicine. Journal of Immunology 186: 4269-77. * Shared Supervision
. Additional Links: erratum.
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Garcia BL, Ramyar KX, Tzekou A, Ricklin D, McWhorter WJ, Lambris JD, Geisbrecht BV. (2010). Molecular basis for complement recognition and inhibition determined by crystallographic studies of the staphylococcal complement inhibitor (SCIN) bound to C3c and C3b. Journal of Molecular Biology 402: 17-29.
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Hamad OA, Nilsson PH, Lasaosa M, Ricklin D, Lambris JD, Nilsson B, Ekdahl KN. (2010). Contribution of chondroitin sulfate A to the binding of complement proteins to activated platelets. PloS one 5: e12889 .
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Qu H, Magotti P, Ricklin D, Wu EL, Kourtzelis I, Wu YQ, Kaznessis YN, Lambris JD. (2011). Novel analogues of the therapeutic complement inhibitor compstatin with significantly improved affinity and potency. Molecular Immunology 48: 481-9.
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Forneris F, Ricklin D, Wu J, Tzekou A, Wallace RS, Lambris JD, Gros P. (2011). Structures of C3b in complex with factors B and D give insight into complement convertase formation. Science 330: 1816-20. Additional Links: Supplementary Information.
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Knerr PJ, Tzekou A, Ricklin D, Qu H, Chen H, van der Donk WA, Lambris JD. (2011). Synthesis and activity of thioether-containing analogues of the complement inhibitor compstatin. ACS Chemical Biology 6: 753-60.
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Garcia BL, Summers BJ, Lin Z, Ramyar KX, Ricklin D, Kamath DV, Fu ZQ, Lambris JD, Geisbrecht BV. (2012). Diversity in the C3b Convertase Contact Residues and Tertiary Structures of the Staphylococcal Complement Inhibitor (SCIN) Protein Family. The Journal of Biological Chemistry 287: 628-40.
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Qu H, Ricklin D, Bai H, Chen H, Reis ES, Maciejewski M, Tzekou A, Deangelis RA, Resuello RR, Lupu F, Barlow PN, Lambris JD. (2013). New analogs of the clinical complement inhibitor compstatin with subnanomolar affinity and enhanced pharmacokinetic properties. Immunobiology 218: 496-505. Additional Links: Supplement.
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Yang K, Deangelis RA, Reed JE, Ricklin D, Lambris JD. (2012). Complement in action: an analysis of patent trends from 1976 through 2011. Advances in Experimental Medicine and Biology 734: 301-13.
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Garcia BL, Summers BJ, Ramyar KX, Tzekou A, Lin Z, Ricklin D, Lambris JD, Laity JH, Geisbrecht BV. (2013). A Structurally Dynamic N-terminal Helix Is a Key Functional Determinant in Staphylococcal Complement Inhibitor (SCIN) Proteins. The Journal of Biological Chemistry 288: 2870-81.
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Abe T, Hosur KB, Hajishengallis E, Reis ES, Ricklin D, Lambris JD, Hajishengallis G. (2012). Local complement-targeted intervention in periodontitis: proof-of-concept using a C5a receptor (CD88) antagonist. Journal of immunology 189: 5442-8.
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Reis ES, Chen H, Sfyroera G, Monk PN, Köhl J, Ricklin D, Lambris JD. (2012). C5a receptor-dependent cell activation by physiological concentrations of desarginated c5a: insights from a novel label-free cellular assay. Journal of Immunology 189: 4797-805. Additional Links: In this Issue.
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Kourtzelis I, Rafail S, DeAngelis RA, Foukas PG, Ricklin D, Lambris JD. (2013). Inhibition of biomaterial-induced complement activation attenuates the inflammatory host response to implantation. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 27: 2768-76.
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Nilsson PH, Ekdahl KN, Magnusson PU, Qu H, Iwata H, Ricklin D, Hong J, Lambris JD, Nilsson B, Teramura Y. (2012). Autoregulation of thromboinflammation on biomaterial surfaces by a multicomponent therapeutic coating. Biomaterials 34: 985-94.
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Yang K, Dinasarapu AR, Reis ES, Deangelis RA, Ricklin D, Subramaniam S, Lambris JD. (2013). CMAP: Complement Map Database. Bioinformatics 29: 1832-3.
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Klapper Y, Hamad OA, Teramura Y, Leneweit G, Nienhaus GU, Ricklin D, Lambris JD, Ekdahl KN, Nilsson B. (2014). Mediation of a non-proteolytic activation of complement component C3 by phospholipid vesicles. Biomaterials 35: 3688-96.
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Oikonomopoulou K, DeAngelis RA, Chen H, Diamandis EP, Hollenberg MD, Ricklin D, Lambris JD. (2013). Induction of complement C3a receptor responses by kallikrein-related peptidase 14. Journal of Immunology 191: 3858-66.
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Risitano AM, Ricklin D, Huang Y, Reis ES, Chen H, Ricci P, Lin Z, Pascariello C, Raia M, Sica M, Del Vecchio L, Pane F, Lupu F, Notaro R, Resuello RR, Deangelis RA, Lambris JD. (2014). Peptide inhibitors of C3 activation as a novel strategy of complement inhibition for the treatment of paroxysmal nocturnal hemoglobinuria. Blood 123: 2094-101. Additional Links: Inside Blood.
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Petrou PS, Ricklin D, Zavali M, Raptis I, Kakabakos SE, Misiakos K, Lambris JD. (2009). Real-time label-free detection of complement activation products in human serum by white light reflectance spectroscopy. Biosensors & Bioelectronics 24: 3359-64.
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Schmidt CQ, Bai H, Lin Z, Risitano AM, Barlow PN, Ricklin D, Lambris JD. (2013). Rational engineering of a minimized immune inhibitor with unique triple-targeting properties. Journal of Immunology 190: 5712-21.
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Woehl JL, Stapels DA, Garcia BL, Ramyar KX, Keightley A, Ruyken M, Syriga M, Sfyroera G, Weber AB, Zolkiewski M, Ricklin D, Lambris JD, Rooijakkers SH, Geisbrecht BV. (2014). The Extracellular Adherence Protein from Staphylococcus aureus Inhibits the Classical and Lectin Pathways of Complement by Blocking Formation of the C3 Proconvertase. Journal of immunology (Baltimore, Md. : 1950) 193: 6161-71.
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Huang Y, Reis ES, Knerr PJ, van der Donk WA, Ricklin D, Lambris JD. (2014). Conjugation to albumin-binding molecule tags as a strategy to improve both efficacy and pharmacokinetic properties of the complement inhibitor compstatin. ChemMedChem 9: 2223-6.
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Maekawa T, Abe T, Hajishengallis E, Hosur KB, DeAngelis RA, Ricklin D, Lambris JD, Hajishengallis G. (2014). Genetic and intervention studies implicating complement C3 as a major target for the treatment of periodontitis. Journal of Immunology 192: 6020-7.
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Reis ES, DeAngelis RA, Chen H, Resuello RR, Ricklin D, Lambris JD. (2015). Therapeutic C3 inhibitor Cp40 abrogates complement activation induced by modern hemodialysis filters. Immunobiology 220: 476-82.
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Kourtzelis I, Ferreira A, Mitroulis I, Ricklin D, Bornstein SR, Waskow C, Lambris JD, Chavakis T. (2015). Complement inhibition in a xenogeneic model of interactions between human whole blood and porcine endothelium. Hormone and Metabolic 47: 36-42.
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Rafail S, Kourtzelis I, Foukas PG, Markiewski MM, DeAngelis RA, Guariento M, Ricklin D, Grice EA, Lambris JD. (2015). Complement deficiency promotes cutaneous wound healing in mice. Journal of Immunology 194: 1285-91.
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Sfyroera G, Ricklin D, Reis ES, Chen H, Wu EL, Kaznessis YN, Ekdahl KN, Nilsson B, Lambris JD. (2015). Rare Loss-of-Function Mutation in Complement Component C3 Provides Insight into Molecular and Pathophysiological Determinants of Complement Activity. Journal of Immunology :.
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Zhang Y, Shao D, Ricklin D, Hilkin BM, Nester CM, Lambris JD, Smith RJ. (2015). Compstatin analog Cp40 inhibits complement dysregulation in vitro in C3 glomerulopathy. Immunobiology 220: 993-8.
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Wang J, Wang L, Xiang Y, Ricklin D, Lambris JD, Chen G. (2015). Using an in vitro xenoantibody-mediated complement-dependent cytotoxicity model to evaluate the complement inhibitory activity of the peptidic C3 inhibitor Cp40. Clinical immunology (Orlando, Fla.) 162: 37-44.
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Lin Z, Schmidt CQ, Koutsogiannaki S, Ricci P, Risitano AM, Lambris JD, Ricklin D. (2015). Complement C3dg-mediated erythrophagocytosis: implications for paroxysmal nocturnal hemoglobinuria. Blood 126: 891-4.
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Georgoutsou-Spyridonos M, Ricklin D, Pratsinis H, Perivolioti E, Pirmettis I, Garcia BL, Geisbrecht BV, Foukas PG, Lambris JD, Mastellos DC, Sfyroera G. (2015). Attenuation of Staphylococcus aureus-Induced Bacteremia by Human Mini-Antibodies Targeting the Complement Inhibitory Protein Efb. Journal of Immunology 195: 3946-58. Additional Links: Top 10% of October 2015.
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Harder MJ, Anliker M, Höchsmann B, Simmet T, Huber-Lang M, Schrezenmeier H, Ricklin D, Lambris JD, Barlow PN, Schmidt CQ. (2016). Comparative Analysis of Novel Complement-Targeted Inhibitors, MiniFH, and the Natural Regulators Factor H and Factor H-like Protein 1 Reveal Functional Determinants of Complement Regulation. Journal of Immunology 196: 866-76.
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Maekawa T, Briones RA, Resuello RR, Tuplano JV, Hajishengallis E, Kajikawa T, Koutsogiannaki S, Garcia CA, Ricklin D, Lambris JD, Hajishengallis G. (2016). Inhibition of pre-existing natural periodontitis in non-human primates by a locally administered peptide inhibitor of complement C3. Journal of Clinical Periodontology :.
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Schmidt CQ, Harder MJ, Nichols EM, Hebecker M, Anliker M, Höchsmann B, Simmet T, Csincsi Á, Uzonyi B, Pappworth IY, Ricklin D, Lambris JD, Schrezenmeier H, Józsi M, Marchbank KJ. (2016). Selectivity of C3-opsonin targeted complement inhibitors: A distinct advantage in the protection of erythrocytes from paroxysmal nocturnal hemoglobinuria patients. Immunobiology 221: 503-11.
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Forneris F, Wu J, Xue X, Ricklin D, Lin Z, Sfyroera G, Tzekou A, Volokhina E, Granneman JC, Hauhart R, Bertram P, Liszewski MK, Atkinson JP, Lambris JD, Gros P. (2016). Regulators of complement activity mediate inhibitory mechanisms through a common C3b-binding mode. The EMBO Journal 35: 1133-49.
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Blatt AZ, Saggu G, Kulkarni KV, Cortes C, Thurman JM, Ricklin D, Lambris JD, Valenzuela JG, Ferreira VP. (2016). Properdin-Mediated C5a Production Enhances Stable Binding of Platelets to Granulocytes in Human Whole Blood. Journal of Immunology 196: 4671-80.
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Lindorfer MA, Cook EM, Reis ES, Ricklin D, Risitano AM, Lambris JD, Taylor RP. (2016). Compstatin Cp40 blocks hematin-mediated deposition of C3b fragments on erythrocytes: Implications for treatment of malarial anemia. Clinical immunology 171: 32-35.
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Primikyri A, Papanastasiou M, Sarigiannis Y, Koutsogiannaki S, Reis ES, Tuplano JV, Resuello RR, Nilsson B, Ricklin D, Lambris JD. (2016). Method development and validation for the quantitation of the complement inhibitor Cp40 in human and cynomolgus monkey plasma by UPLC-ESI-MS. Journal of Chromatography B. Analytical Technologies in the Biomedical and Life Sciences 1041-1042: 19-26.
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Harder MJ, Kuhn N, Schrezenmeier H, Höchsmann B, von Zabern I, Weinstock C, Simmet T, Ricklin D, Lambris JD, Skerra A, Anliker M, Schmidt CQ. (2016). Incomplete inhibition by eculizumab: mechanistic evidence for residual C5 activity during strong complement activation. Blood :.
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Papanastasiou M, Koutsogiannaki S, Sarigiannis Y, Geisbrecht BV, Ricklin D, Lambris JD. (2017). Structural Implications for the Formation and Function of the Complement Effector Protein iC3b. Journal of immunology :.
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Knecht S, Ricklin D, Eberle AN, Ernst B. (2009). Oligohis-tags: mechanisms of binding to Ni2+-NTA surfaces. Journal of molecular recognition 22: 270-9.
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Qu H, Ricklin D, Lambris JD. (2009). Recent developments in low molecular weight complement inhibitors. Molecular immunology 47: 185-95.
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Stokmaier D, Khorev O, Cutting B, Born R, Ricklin D, Ernst TO, Böni F, Schwingruber K, Gentner M, Wittwer M, Spreafico M, Vedani A, Rabbani S, Schwardt O, Ernst B. (2009). Design, synthesis and evaluation of monovalent ligands for the asialoglycoprotein receptor (ASGP-R). Bioorganic & medicinal chemistry 17: 7254-64.
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Herfurth L, Ernst B, Wagner B, Ricklin D, Strasser DS, Magnani JL, Benie AJ, Peters T. (2005). Comparative epitope mapping with saturation transfer difference NMR of sialyl Lewis(a) compounds and derivatives bound to a monoclonal antibody. Journal of medicinal chemistry 48: 6879-86.
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